The purpose of this Catalyst project is to apply a highly innovative general theory that integrates evolution, developmental biology, and epigenetics, to metabolic disease and diabetes. The underling premise is that intrinsic variability in phenotype from individual to individual, even with an identical genome, is not simply noise, but is itself in part a signal with adaptive value in evolution, development, and response to the environment. Moreover, this variability is mediated through the epigenome, has profound effects on metabolism, and is in turn affected by metabolic signals in the environment during development. If this hypothesis is even in part correct, the proposed work would provide at least partial solutions to arguably two of the most important problems facing NIDDK, and NIH as a whole: (1) How can we apply genetic testing, or precision medicine more generally, if the intrinsic variability from person to person is great, even with ideally complete genetic knowledge? and (2) Is data irreproducibility in fact driven partly by inherent and adaptive variability that carries information of critical diagnostic and therapeutic importance? This provocative idea has transformative implications for how we approach the application of precision medicine to address the growing incidence of obesity and metabolic syndrome. Existing data using reproducible genomes, such as inbred or F1 hybrid mice, in highly controlled environments, clearly shows the existing of inherent variability in metabolic phenotypes. To elucidate the underlying origins of this variability and to develop a paradigm to exploit this knowledge to improve the accuracy of precision medicine as applied to metabolic disease, we will (1) measure the degree of phenotypic plasticity in genetically identical mice, testing within-litter inter-mouse variability, inter-litter variability, and inter-strain variability; (2) determine the effect of prenatal nutritional perturbation on phenotypic and epigenetic plasticity; (3) translate these findings to assessing the accuracy of human metabolic disease precision medicine; and (4) investigate sex differences in epigenomic and phenotypic variability. This highly innovative proposal represents a completely new direction for my research, and could have profound influence on our understanding of the developmental origins and associated variability in susceptibility to metabolic disease, with profound implications on future interventions using precision medicine paradigms.